CN104703981A - Benzimidazol.es as CNS active agents - Google Patents

Benzimidazol.es as CNS active agents Download PDF

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CN104703981A
CN104703981A CN201380050747.1A CN201380050747A CN104703981A CN 104703981 A CN104703981 A CN 104703981A CN 201380050747 A CN201380050747 A CN 201380050747A CN 104703981 A CN104703981 A CN 104703981A
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phenyl
benzoglyoxaline
pyrazole
fluoro
chloro
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CN104703981B (en
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西蒙娜·M·切卡雷利
拉维·姚高希亚
罗兰·雅各布-勒特
于尔根·维希曼
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F Hoffmann La Roche AG
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Abstract

The present invention relates to compounds of general formula wherein R1 hydrogen, lower alkyl, halogen or lower alkyl substituted by halogen; R2 is hydrogen or halogen; X1 is N or CH; X2 is N or CH; with the proviso that only one of X1 or X2 is N; X3 is C(R) or N; and R is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen, lower alkoxy or SO2-lower alkyl; or to a pharmaceutically acceptable acid addition salt, to a racemic mixture or to its corresponding enantiomer and/or optical isomers thereof. The compounds may be used for the treatment of schizophrenia, obsessive-compulsive personality disorder, major depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, mild cognitive impairment, chemotherapy-induced cognitive dysfunction, Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine and cocaine.

Description

As the benzimidazoles compound of CNS activity medicament
The present invention relates to the compound of following general formula
Wherein
R 1hydrogen, low alkyl group, halogen or the low alkyl group be optionally substituted by halogen;
R 2it is hydrogen or halogen;
X 1n or CH;
X 2n or CH;
Precondition is X 1or X 2in only one be N;
X 3c (R) or N;
And R is hydrogen, low alkyl group, halogen, the low alkyl group be optionally substituted by halogen, lower alkoxy or SO 2-low alkyl group;
Or relate to its medicinal acid addition salt, racemic mixture or its corresponding enantiomer and/or optical isomer.
Show now, compound stimulation of the present invention occurs from the nerve of neural stem cell (NSCs).Nerve occurs in growth course and is neutralized in human brain and occurs.Conceptive, this process of neurogenesis can be divided into four steps: the propagation of (i) NSCs; (ii) neuron fates of NSC determines; (iii) new neuronic survival and maturation; (iv) new neuronal function is integrated into neural network.
Adult neural is the growth course occurred in Adult Human Brain in whole life, and whereby, new functional neurosurgery unit produces from adult neural stem cell.Composing type adult neural occurs mainly to occur in two " neurogenic " brain regions in physiological conditions, 1) the submicron particle district (SGZ) in hippocampal dentate, produce new dentation granulosa cell there, 2) the sub-ventricles of the brain district (SVZ) of tricorn, neurone new there produces and migrates to olfactory bulb by rostral migration stream (RMS) subsequently, thus becomes relay cell.
Evidence implicates widely, the adult neural of hippocampus occurs in cognitive and emotional state and plays a significant role, although accurate function is still difficult to obtain.Argue, new grain neurone relatively in a small amount can affect whole brain function, because they make a lot of relay cells in dentate gyrus innervate, its each suppression hundreds of ripe granulosa cells, cause the dependent feedback inhibition of neural generation.Combine with low excitation threshold, described newborn neuron causes response for change very trickle in environment.Imbalance in this process can show the shortage on the modal cutoff relevant to mental disorder in behavior.Such as, the nerve of adult hippocampal occurs relevant with emotional ability to cognition, such as, physical activity, being exposed to abundant external environment and typical thymoleptic promotes adult hippocampal's nerve to occur and cognitive and/or emotional state concomitantly, chronic stress (chronic stress) simultaneously, dysthymia disorders, sleep deprivation and the old and feeble adult neural of minimizing occur and to negative cognition with and/or the relevant (Neuron 70 of emotional state, on May 26th, 2011, pp 582-588 and pp 687-702; WO2008/046072).Interestingly, there is the generation and its impact on some behavior needs excite nerve in thymoleptic promotion hippocampus adult neural.Usually believe, be very limited under the nerve in other adult CNS region occurs in normal physiological conditions, but damaging such as apoplexy (stroke), and can be induced after maincenter and periphery brain injury.
Therefore, it is believed that, the stimulation that adult neural occurs represents for usual aging and the treatment of nerve regeneration target spot in particular for multiple neurodegenerative disease and neuropsychiatric disease, described neurodegenerative disease and neuropsychiatric disease comprise schizophrenia (schizophrenia), compulsive personality disorder (obsessive-compulsive personality disorder), major depressive disorder (major depression), bipolar disorder (bipolar disorders), anxiety disorder (anxiety disorders), epilepsy (epilepsy), retinal degeneration (retinal degeneration), traumatic brain injury (traumatic brain injury), Spinal injury (spinal cord injury), post-traumatic stress disorder (post-traumatic stressdisorder), panic disorder (panic disorder), Parkinson's disease (Parkinson's disease), dull-witted (dementia), alzheimer's disease (Alzheimer ' s disease), mild cognitive impairment (mildcognitive impairment), the cognition dysfunction (chemotherapy-inducedcognitive dysfunction) (" after chemotherapy brain (chemobrain) ") that chemotherapy causes, mongolism (Downsyndrome), autism spectrum disorder (autism spectrum disorders), hearing loss (hearingloss) (Neuroscience, 167 (2010) 1216-1226, Nature Medicine, 11st volume, 3rd phase, (2005), 271-276) tinnitus (tinnitus), spinocebellar ataxia (spinocerebellarataxia), amyotrophic lateral sclerosis (amyotrophic lateral sclerosis), multiple sclerosis (multiple sclerosis), Huntington Chorea (Huntington ' s disease), apoplexy (stroke), with by radiotherapy (radiation therapy), chronic stress (chronic stress), or neuroactive drug such as alcohol, opiate, methyl amphetamine, the imbalance (US2012/0022096) that the abuse of phencyclidine and Cocaine causes.
Therefore, chemical stimulation adult neural provides new regeneration means and chance, to develop the new drug being used for the treatment of nervous system disorders and neuropsychiatric disorders.
Therefore, the object of the invention is qualification and regulate neurogenetic compound.Have been found that, the compound of formula I has activity in this field and therefore they can be used for the treatment of schizophrenia (schizophrenia), compulsive personality disorder (obsessive-compulsive personalitydisorder), major depressive disorder (major depression), bipolar disorder (bipolar disorders), anxiety disorder (anxiety disorders), usual aging, epilepsy (epilepsy), retinal degeneration (retinaldegeneration), traumatic brain injury (traumatic brain injury), Spinal injury (spinal cordinjury), post-traumatic stress disorder (post-traumatic stress disorder), panic disorder (panic disorder), Parkinson's disease (Parkinson ' s disease), dull-witted (dementia), alzheimer's disease (Alzheimer ' s disease), mild cognitive impairment (mild cognitive impairment), the cognition dysfunction (chemotherapy-induced cognitive dysfunction) (" chemobrain ") that chemotherapy causes, mongolism (Down syndrome), autism spectrum disorder (autismspectrum disorders), hearing loss (hearing loss), tinnitus (tinnitus), spinocebellar ataxia (spinocerebellar ataxia), amyotrophic lateral sclerosis (amyotrophic lateralsclerosis), multiple sclerosis (multiple sclerosis), Huntington Chorea (Huntington ' s disease), apoplexy (stroke), with by radiotherapy (radiation therapy), chronic stress (chronic stress), or neuroactive drug such as alcohol, opiate, methyl amphetamine, the imbalance that the abuse of phencyclidine and Cocaine causes.
The most preferred indication of the compound of formula I is alzheimer's disease (Alzheimer ' s disease), dysthymia disorders (depression), anxiety disorder (anxiety disorders) and apoplexy (stroke).
The present invention relates to the compound of formula I and its pharmaceutical salts (when this is applicable to the form of the mixture of enantiomer or diastereomer or its enantiomer or diastereisomericallypure pure), relate to these compounds as pharmaceutically active substances, relate to their production method, and relate to treatment or prophylactic purposes, described disease relates to neural generation, schizophrenia (schizophrenia), compulsive personality disorder (obsessive-compulsive personalitydisorder), major depressive disorder (major depression), bipolar disorder (bipolar disorders), anxiety disorder (anxiety disorders), usual aging, epilepsy (epilepsy), retinal degeneration (retinaldegeneration), traumatic brain injury (traumatic brain injury), Spinal injury (spinal cordinjury), post-traumatic stress disorder (post-traumatic stress disorder), Parkinson's disease (Parkinson's disease), dull-witted (dementia), alzheimer's disease (Alzheimer ' s disease), mild cognitive impairment (mild cognitive impairment), the cognition dysfunction (chemotherapy-induced cognitive dysfunction) that chemotherapy causes, mongolism (Downsyndrome), autism spectrum disorder (autism spectrum disorders), hearing loss (hearingloss), tinnitus (tinnitus), spinocebellar ataxia (spinocerebellar ataxia), amyotrophic lateral sclerosis (amyotrophic lateral sclerosis), multiple sclerosis (multiple sclerosis), Huntington Chorea (Huntington ' s disease), apoplexy (stroke), radiotherapy (radiation therapy), chronic stress (chronic stress), neuroactive drug is alcohol such as, opiate, methyl amphetamine, the abuse of phencyclidine and Cocaine, and the pharmaceutical composition related to containing formula I.
No matter the term discussed occurs alone or in combination, the definition below for the generic term of this specification sheets is all applicable.
As used in this article, term " low alkyl group " expression comprises the saturated of the straight or branched carbochain with 1-4 carbon atom, i.e. aliphatic hydrocarbon group.The example of " alkyl " is methyl, ethyl, n-propyl, and sec.-propyl.
Term " lower alkoxy " represents group-O-R ', and wherein R ' is low alkyl group defined above.
Term " low alkyl group be optionally substituted by halogen " represents low-grade alkyl group defined above and wherein at least one hydrogen atom is substituted by halogen.
Term " halogen " represents chlorine, bromine, fluorine or iodine.
Term " pharmaceutical salts " or " medicinal acid addition salt " comprise inorganic and organic acid salt, all example hydrochloric acids, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, toxilic acid, acetic acid, succsinic acid, tartrate, methylsulfonic acid, to benzene methanesulfonic acid salt etc.
One embodiment of the invention are compounds of formula IA
Wherein
R 1hydrogen, low alkyl group, halogen or the low alkyl group be optionally substituted by halogen;
R 2it is hydrogen or halogen;
X 3c (R) or N;
And R is hydrogen, low alkyl group, halogen, the low alkyl group be optionally substituted by halogen, lower alkoxy or SO 2-low alkyl group;
Or its medicinal acid addition salt, racemic mixture or its corresponding enantiomer and/or optical isomer, such as
The p-tolyl of 1--6-(the p-tolyl of 2--2H-pyrazole-3-yl)-1H-benzoglyoxaline
1-phenyl-6-(2-phenyl-2H-pyrazole-3-yl)-1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-phenyl-1H-benzoglyoxaline
1-phenyl-6-(the p-tolyl of 2--2H-pyrazole-3-yl)-1H-benzoglyoxaline
6-(2-phenyl-2H-pyrazole-3-yl) the p-tolyl of-1--1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl] the p-tolyl of-1--1H-benzoglyoxaline
1-(the fluoro-phenyl of 4-)-6-(2-phenyl-2H-pyrazole-3-yl)-1H-benzoglyoxaline
1-(the fluoro-phenyl of 4-)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
1-(the fluoro-phenyl of 4-)-6-(the p-tolyl of 2--2H-pyrazole-3-yl)-1H-benzoglyoxaline
1-(the fluoro-phenyl of 4-)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(the fluoro-phenyl of 4-)-1H-benzoglyoxaline
1-(the chloro-phenyl of 4-)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
1-(the chloro-phenyl of 4-)-6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-trifluoromethyl-phenyl)-1H-benzoglyoxaline
1-(2,4-difluorophenyl)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(2,4-difluorophenyl)-1H-benzoglyoxaline
1-(2,4-difluorophenyl)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-trifluoromethyl-phenyl)-1H-benzoglyoxaline
1-(the chloro-phenyl of 4-)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-pyridin-4-yl-1H-benzoglyoxaline
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-pyridin-4-yl-1H-benzoglyoxaline
1-(the fluoro-phenyl of the chloro-2-of 4-)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
1-(the fluoro-phenyl of the chloro-2-of 4-)-6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-methoxyl group-phenyl)-1H-benzoglyoxaline
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-methoxyl group-phenyl)-1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-Metlianesulfonyl-phenyl)-1H-benzoglyoxaline, or
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-Metlianesulfonyl-phenyl)-iH-benzoglyoxaline.
A further embodiment of the present invention is the compound of formula IA-1
Wherein
R 1hydrogen, low alkyl group, halogen or the low alkyl group be optionally substituted by halogen;
R 2it is hydrogen or halogen;
R is hydrogen, low alkyl group, halogen, the low alkyl group be optionally substituted by halogen, lower alkoxy or SO 2-low alkyl group;
Or its medicinal acid addition salt, racemic mixture or its corresponding enantiomer and/or optical isomer, such as
The p-tolyl of 1--6-(the p-tolyl of 2--2H-pyrazole-3-yl)-1H-benzoglyoxaline
1-phenyl-6-(2-phenyl-2H-pyrazole-3-yl)-1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-phenyl-1H-benzoglyoxaline
1-phenyl-6-(the p-tolyl of 2--2H-pyrazole-3-yl)-1H-benzoglyoxaline
6-(2-phenyl-2H-pyrazole-3-yl) the p-tolyl of-1--iH-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl] the p-tolyl of-1--1H-benzoglyoxaline
1-(the fluoro-phenyl of 4-)-6-(2-phenyl-2H-pyrazole-3-yl)-1H-benzoglyoxaline
1-(the fluoro-phenyl of 4-)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
1-(the fluoro-phenyl of 4-)-6-(the p-tolyl of 2--2H-pyrazole-3-yl)-1H-benzoglyoxaline
1-(the fluoro-phenyl of 4-)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(the fluoro-phenyl of 4-)-1H-benzoglyoxaline
1-(the chloro-phenyl of 4-)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
1-(the chloro-phenyl of 4-)-6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-trifluoromethyl-phenyl)-1H-benzoglyoxaline
1-(2,4-difluorophenyl)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(2,4-difluorophenyl)-1H-benzoglyoxaline
1-(2,4-difluorophenyl)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-trifluoromethyl-phenyl)-1H-benzoglyoxaline
1-(the chloro-phenyl of 4-)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
1-(the fluoro-phenyl of the chloro-2-of 4-)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
1-(the fluoro-phenyl of the chloro-2-of 4-)-6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-methoxyl group-phenyl)-1H-benzoglyoxaline
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-methoxyl group-phenyl)-1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-Metlianesulfonyl-phenyl)-1H-benzoglyoxaline, or
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-Metlianesulfonyl-phenyl)-1H-benzoglyoxaline.
A further embodiment of the present invention is the compound of formula IA-2
Wherein
R 1hydrogen, low alkyl group, halogen or the low alkyl group be optionally substituted by halogen;
R 2it is hydrogen or halogen;
Or its medicinal acid addition salt, racemic mixture or its corresponding enantiomer and/or optical isomer, such as
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-pyridin-4-yl-1H-benzoglyoxaline, or
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-pyridin-4-yl-1H-benzoglyoxaline.
A further embodiment of the present invention is the compound of formula IB
Wherein
R 1hydrogen, low alkyl group, halogen or the low alkyl group be optionally substituted by halogen;
R 2it is hydrogen or halogen;
X 3c (R) or N;
And R is hydrogen, low alkyl group, halogen, the low alkyl group be optionally substituted by halogen, lower alkoxy or SO 2-low alkyl group;
Or its medicinal acid addition salt, racemic mixture or its corresponding enantiomer and/or optical isomer, such as
1-(the fluoro-phenyl of 4-)-6-(3-phenyl-3H-imidazol-4 yl)-1H-benzoglyoxaline
6-[3-(the chloro-phenyl of 4-)-3H-imidazol-4 yl]-1-(the fluoro-phenyl of 4-)-1H-benzoglyoxaline, or
1-(the fluoro-phenyl of 4-)-6-[3-(the fluoro-phenyl of 4-)-3H-imidazol-4 yl]-1H-benzoglyoxaline.
Can pass through methods known in the art, such as prepared compound and its pharmaceutical salts of formula I of the present invention by method described below, described method comprises
Make the compound of formula 1
With the compound of formula 2
The compound of reacting generating I
Further, if needed, the compound of acquisition is changed into medicinal acid addition salt.
The preparation of the compound of formula I can be carried out with order or the route of synthesis assembled.The compound display of the compounds of this invention is in following scheme 1.The technology of carrying out the product of described reaction and purifying generation is known for those skilled in the art.Unless indicated to the contrary, the substituting group that following methods uses in describing has with mark the meaning above provided.
In more detail, can by the method that hereafter provides, by the method that provides in embodiment or the compound being manufactured formula I by similar approach.The appropriate reaction condition of each reactions steps is well known by persons skilled in the art.Reaction sequence is not limited to the order of display in scheme 1, but depend on parent material and its respective reactivity, the order of reactions steps can arbitrarily change.Parent material be commercially available maybe can by the method similar with the method hereafter provided, the method described in the reference quoted by specification sheets or in embodiment, or prepared by methods known in the art.
scheme 1
The compound of formula IA can prepare (scheme I) by the linked reaction of the bromo-benzoglyoxaline 2 of palladium chtalyst and boric acid 1.
Boric acid 1 is commercially available or can pass through to prepare from corresponding phenyl imidazole 6 with n-Butyl Lithium and triisopropyl borate ester process at-78 DEG C.If not commercially available, then phenyl imidazole 6 can be prepared from corresponding phenyl-hydrazine 5.
Bromo-benzoglyoxaline 2 can be prepared in the following way: the fluoro-oil of mirbane of bromo-for 4-2-7 and corresponding aniline 8 are reacted, then nitryl group is reduced, produce 1,2-diamino-benzene derivative 9, it is subsequently by changing into benzoglyoxaline 2 with trimethyl orthoformate and formic acid process.
scheme 2
The imdazole derivatives of relevant formula IB can easily be prepared (scheme 2) by the bromo-benzoglyoxaline 3 of palladium chtalyst and the linked reaction of commercially available phenyl imidazole 4.
the abstraction and purification of compound
If needed, the abstraction and purification of compound described herein and intermediate can be undertaken by the isolated or purified method of any appropriate, described method such as, such as, is filtered, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, the combination of preparative low or high pressure liquid chromatography or these methods.Suitable separation and the illustrating of isolation process can be obtained by reference to preparation hereafter and embodiment.But, certainly can use other suitable separation or isolation process.The racemic mixture of the chipal compounds of chirality HPLC separate type I can be used.
the salt of the compound of formula I
The compound of formula I is alkalescence and can be converted into respective acids additive salt.By all example hydrochloric acids of suitable acid by least stoichiometric amount, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc., and organic acid such as acetic acid, propionic acid, oxyacetic acid, pyruvic acid, oxalic acid, oxysuccinic acid, propanedioic acid, succsinic acid, toxilic acid, fumaric acid, tartrate, citric acid, phenylformic acid, styracin, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, the process such as Whitfield's ointment realizes changing.Typically, free alkali is dissolved in inert organic solvents such as diethyl ether, ethyl acetate, chloroform, in ethanol or methyl alcohol etc., and acid is added in similar solvent.Temperature is maintained between 0 DEG C and 50 DEG C.The salt spontaneous precipitation produced maybe can take solution out of with the solvent of less polarity.
The acid salt of the basic cpd of formula I can by using suitable the alkali such as sodium hydroxide or potassium hydroxide of at least stoichiometric equivalents, salt of wormwood, sodium bicarbonate, and the process such as ammoniacal liquor changes corresponding free alkali into.
Compound and its acceptable addition salt of formula I have useful pharmaceutical properties.Particularly, have been found that compound of the present invention has the activity as neurogenic agent.
Compound according to the testing research hereafter provided.
Nerve measures
cell proliferation of nerve cord measures
Micromolecular neurogenic character suppresses the propagation of the neural stem cell (NSCs) of derivative derived from human embryonic stem based on the dual smad by describing before and determines (Chambers, S.M., Deng people, Highly efficient neural conversion of human ES and iPS cells by dualinhibition of SMAD signaling, Nature biotechnology, 2009.27 (3): p.275-80.)
After the incubation period of 4 days by increasing based on the cell of ATP level (Promega: ) measure compound response.
NSCs is thawed and expanded for 3 generations.At the 14th day, by NSCs with 21 ' 000 cell/cm in 38 μ l culture volumes 2cell density inoculate in 384 orifice plates of Polyornithin/Laminin bag quilt.
Latter 4 hours of cell inoculation, adds compound solution with the volume of 2 μ l.By the dilution of the liquid storage (water, 5%DMSO) of compound to obtain dose response (11 points, dilution factor is 2), scope is from 8 μMs to 8nM.Run contrast with the neurogenic character constantly determining cell:
Negative (neutrality) contrast be cell culture medium (final DMSO concentration: 0.25%).
Positive control is:
1. cell culture medium+100ng/ml FGF2 (final DMSO concentration: 0.1%)
2. cell culture medium+20ng/ml EGF (final DMSO concentration: 0.1%)
3. cell culture medium+100ng/ml Wnt3a (final DMSO concentration: 0.1%)
At 37 DEG C, 5%CO 2after hatching 4 days, the ATP amount in quantitatively every hole.ATP concentration and cell quantity proportional.By using Promega kit ATP. reagent contains Cell lysis buffer, thermally-stabilised luciferase (UltraGlo tMrestructuring luciferase), magnesium and fluorescein.Fluorescein and ATP react and produce oxyluciferin, AMP and light.Luminous signal and ATP content proportional.
For each assay plate, on average determine feminine gender (neutrality) control value by what adopt 16 negative control holes.For each compound, be (compound/negative control) * 100 by neurogenic compound RESPONSE CALCULATION.
For each test compounds, determine the EC from dose response curve 150value.EC 150it is the compound concentration of 150% activity reaching contrast (100%).
Preferred compound is presented at the EC in the scope of < 2.8 μMs 150(μM), as shown in the table.
embodiment and EC 150 data sheet
intermediate
Intermediate A: 1-(4-fluorophenyl)-1H-pyrazoles-5-ylboronic acid
Under nitrogen atmosphere at-78 DEG C, to commercially available 1-(4-fluorophenyl)-1H-pyrazoles [CAS No81329-32-0] (1.6g, n-Butyl Lithium (1.6N is dropwise added in stirred solution 9.87mmol) in THF (39.5ml), in hexane, 6.47ml, 10.4mmol).After making mixture stir 1h at-78 DEG C, add triisopropyl borate ester (7.65g, 9.35ml, 39.5mmol) at-78 DEG C.Make mixture stir 1h at-78 DEG C, be warmed to room temperature gradually, and with 1M HCl solution by the pH regulator to 5 of mixture.Evaporate this mixture and remaining aqueous layer with ethyl acetate (2x 30ml) is extracted.Organic layer washed with brine (30ml) washing merged, uses MgSO 4drying is also evaporated.Crude product is by silica gel column chromatography (methylene dichloride/MeOH) and grinding (diethyl ether/hexane) purifying, obtain title compound, for white solid (479mg, 24%), MS (ISN) m/z=205.0 [(M-H) -], mp 115 DEG C.
Intermediate B: 1-(p-methylphenyl)-1H-pyrazoles-5-ylboronic acid
This title compound, pale solid (629mg, 37%), MS (ISN) m/z=201.2 [(M-H) -], mp 111 DEG C, the universal method according to intermediate A is prepared from commercially available 1-(p-methylphenyl)-1H-pyrazoles [CAS No.20518-17-6] (1.35g, 8.53mmol) and triisopropyl borate ester.
Intermediate C:1-(4-(trifluoromethyl)-phenyl)-1H-pyrazoles-5-ylboronic acid
This title compound, brown solid (2.26g, 62%), MS (ISN) m/z=255.5 [(M-H) -], mp 306 DEG C, the universal method according to intermediate A is prepared from commercially available 1-(4-(trifluoromethyl)-phenyl)-1H-pyrazoles [CAS No.207797-05-5] (3g, 14.1mmol) and triisopropyl borate ester.
Intermediate D:1-(4-chloro-phenyl-)-1H-pyrazoles-5-ylboronic acid
This title compound, brown solid (400mg, 17%), MS (ISN) m/z=221.2 [(M-H) -], the universal method according to intermediate A is prepared from commercially available 1-(4-chloro-phenyl-)-1H-pyrazoles [CASNo.25419-86-7] (1.87g, 10.5mmol) and triisopropyl borate ester.
The bromo-1-phenyl of intermediate E: 6--1H-benzo [d] imidazoles
steps A
To the fluoro-1-oil of mirbane of the bromo-2-of commercially available 4-(1g, 4.47mmol) with salt of wormwood (680mg, the middle interpolation aniline (419mg that stirs the mixture 4.92mmol) in DMSO (17.9ml), 410 μ l, 4.47mmol) and make reaction mixture at stirring at room temperature 65h.Reaction mixture is poured into also ethyl acetate (2x 70ml) extraction in water (100ml).Organic layers with water (1x 50ml) washing merged, dry (MgSO 4) and evaporate.Crude product (orange solids, 1.32g) by flash chromatography [heptane/ethyl acetate (the 0-10%)] purifying on silica gel, obtain orange solids (1.06g, 3.62mmol), be dissolved in subsequently in methyl alcohol (50.0ml).To in stirred solution, add hydrochloric acid (37%, 50ml) and tin chloride (II) dihydrate (4.9g, 21.7mmol) in room temperature, make reaction mixture stir 1h at 80 DEG C afterwards.Reaction mixture is evaporated, add ice and 3N sodium hydroxide solution (50ml), and mixture ethyl acetate (2x100ml) extracts.Organic layer washed with brine (50ml) washing merged, dry (MgSO 4) and evaporate.Crude product (0.94g) is by flash chromatography (heptane/ethyl acetate 4: the 1) purifying on silica gel, obtaining 4-bromo-N2-phenyl-benzene-1,2-diamines, is brown solid (429mg, 36%), MS (ISN) m/z=261.0 [(M-H) -], mp 103 DEG C.
step B
To the bromo-N2-phenyl-benzene-1 of 4-, 2-diamines (steps A) (420mg, 1.6mmol) with trimethyl orthoformate (4.8g, 5ml, in stirring the mixture 45.2mmol), add formic acid (1.2g, 1ml in room temperature, 26.1mmol), reaction mixture is made under reflux conditions to stir 2h afterwards.Reaction mixture is cooled to room temperature, evaporates and use ethyl acetate (2x 40ml) to extract.The organic layer merged saturated sodium bicarbonate solution (20ml) and salt solution (20ml) washing, dry (MgSO 4) and evaporate.Crude product (400mg) is by flash chromatography (heptane/ethyl acetate 3: the 2) purifying on silica gel, obtain title compound, for pale solid (358mg, 82%), MS (ISP) m/z=275.0 [(M+H) +].
The p-tolyl of the bromo-1-of intermediate F:6--1H-benzo [d] imidazoles
steps A
The bromo-N2-of 4-p-tolyl-benzene-1,2-diamines, orange (0.95g, 76%), MS (ISN) m/z=275.1 [(M-H) -], the universal method (steps A) according to intermediate E is prepared from the fluoro-1-oil of mirbane (1g, 4.47mmol) of the bromo-2-of commercially available 4-and p-toluidine (484mg, 4.47mmol).
step B
This title compound, light brown oil thing (854mg, 88%), MS (ISP) m/z=289.0 [(M+H) +], the universal method (step B) according to intermediate E is prepared from the bromo-N2-of 4-p-tolyl-benzene-1,2-diamines (steps A) (0.94g, 3.39mmol).
The bromo-1-of intermediate G:6-(the fluoro-phenyl of 4-)-1H-benzo [d] imidazoles
steps A
The bromo-N2-of 4-(the fluoro-phenyl of 4-)-benzene-1,2-diamines, brown oil (0.83g, 33%), MS (ISN) m/z=281.1 [(M-H) -], the universal method (steps A) according to intermediate E is prepared from the fluoro-aniline (1.02g, 8.94mmol) of commercially available 4-bromo-2-fluoro-1-oil of mirbane (2g, 8.94mmol) and 4-.
step B
This title compound, pale solid (751mg, 88%), MS (ISP) m/z=293.0 [(M+H) +], mp 111.5 DEG C, the universal method (step B) according to intermediate E is prepared from the bromo-N2-of 4-(the fluoro-phenyl of 4-)-benzene-1,2-diamines (steps A) (0.82g, 2.92mmol).
The bromo-1-of intermediate H:6-(the chloro-phenyl of 4-)-1H-benzo [d] imidazoles
steps A
The bromo-N2-of 4-(the chloro-phenyl of 4-)-benzene-1,2-diamines, light brown oil thing (0.9g, 41%), MS (ISP) m/z=299.3 [(M+H)+], universal method (steps A) according to intermediate E is prepared from the chloro-aniline (0.97g, 7.38mmol) of commercially available 4-bromo-2-fluoro-1-oil of mirbane (1.5g, 6.71mmol) and 4-.
step B
This title compound, brown solid (492mg, 53%), MS (ISP) m/z=309.3 [(M+H) +], mp 131 DEG C, the universal method (step B) according to intermediate E is prepared from the bromo-N2-of 4-(the chloro-phenyl of 4-)-benzene-1,2-diamines (steps A) (0.9g, 3.02mmol).
The bromo-1-of intermediate compound I: 6-(4-trifluoromethyl-phenyl)-1H-benzo [d] imidazoles
steps A
The bromo-N2-of 4-(4-trifluoromethyl-phenyl)-benzene-1,2-diamines, brown solid (0.46g, 21%), MS (ISP) m/z=331.3 [(M+H) +], mp 84 DEG C, the universal method (steps A) according to intermediate E is prepared from the fluoro-1-oil of mirbane (1.5g, 6.71mmol) of the bromo-2-of commercially available 4-and 4-trifluoromethyl-aniline (1.23g, 7.38mmol).
step B
This title compound, brown solid (461mg, 97%), MS (ISP) m/z=341.3 [(M+H) +], mp 84.5 DEG C, the universal method (step B) according to intermediate E is prepared from the bromo-N2-of 4-(4-trifluoromethyl-phenyl)-benzene-1,2-diamines (steps A) (0.46g, 1.39mmol).
The bromo-1-of intermediate K:6-(2,4-difluorophenyl)-1H-benzo [d] imidazoles
steps A
The bromo-N2-of 4-(2,4-difluorophenyl)-benzene-1,2-diamines, brown solid (1.98g, 73%), MS (ISP) m/z=299.3 [(M+H) +], mp 77 DEG C, the universal method (steps A) according to intermediate E is prepared from the fluoro-1-oil of mirbane (2g, 9.09mmol) of the bromo-2-of commercially available 4-and 2,4-difluoro-aniline (2.35g, 18.2mmol).
step B
This title compound, brown solid (2.0g, 98%), MS (ISP) m/z=309.3 [(M+H) +], mp 84 DEG C, the universal method (step B) according to intermediate E is prepared from the bromo-N2-of 4-(2,4-difluorophenyl)-benzene-1,2-diamines (steps A) (1.98g, 6.62mmol).
The bromo-1-pyridin-4-yl of intermediate L:6--1H-benzoglyoxaline
steps A
4-bromo-N2-pyridin-4-yl-benzene-1,2-diamines, white solid (0.31g, 30%), MS (ISP) m/z=266.3 [(M+H) +], mp 137.5 DEG C, the universal method (steps A) according to intermediate E is prepared from the fluoro-1-oil of mirbane (0.865g, 3.93mmol) of the bromo-2-of commercially available 4-and 4-amino-pyridine (0.37g, 3.93mmol).
step B
This title compound, white solid (207mg, 67%), MS (ISP) m/z=274.3 [(M+H) +], mp 132 DEG C, the universal method (step B) according to intermediate E is prepared from 4-bromo-N2-pyridin-4-yl-benzene-1,2-diamines (steps A) (0.3g, 1.14mmol).
The bromo-1-of intermediate M:6-(the fluoro-phenyl of the chloro-2-of 4-)-1H-benzo [d] imidazoles
steps A
The bromo-N2-of 4-(the fluoro-phenyl of the chloro-2-of 4-)-benzene-1,2-diamines, light brown oil thing (1.4g, 49%), MS (ISP) m/z=317.3 [(M+H) +], the universal method (steps A) according to intermediate E is prepared from the fluoro-aniline (2.65g, 18.2mm01) of the chloro-2-of commercially available 4-bromo-2-fluoro-1-oil of mirbane (2g, 9.09mmol) and 4-.
step B
This title compound, pale solid (1.33g, 92%), MS (ISP) m/z=327.3 [(M+H) +], mp 154 DEG C, the universal method (step B) according to intermediate E is prepared from the bromo-N2-of 4-(the fluoro-phenyl of the chloro-2-of 4-)-benzene-1,2-diamines (steps A) (1.4g, 4.44mmol).
The bromo-1-of intermediate N:6-(4-methoxyl group-phenyl)-1H-benzo [d] imidazoles
steps A
The bromo-N2-of 4-(4-methoxyl group-phenyl)-benzene-1,2-diamines, dark red solid (2.48g, 93%), MS (ISP) m/z=293.4 [(M+H) +], mp 96 DEG C, the universal method (steps A) according to intermediate E is prepared from the fluoro-1-oil of mirbane (2.0g, 9.09mmol) of the bromo-2-of commercially available 4-and 4-methoxy-pllenylamine (2.24g, 18.2mmol).
step B
This title compound, light pink solid (2.3g, 90%), MS (ISP) m/z=305.4 [(M+H) +], mp 122 DEG C, the universal method (step B) according to intermediate E is prepared from the bromo-N2-of 4-(4-methoxyl group-phenyl)-benzene-1,2-diamines (steps A) (2.47g, 8.43mmol).
The bromo-1-of intermediate O:6-(4-Metlianesulfonyl-phenyl)-1H-benzo [d] imidazoles
steps A
The bromo-N2-of 4-(4-Metlianesulfonyl-phenyl)-benzene-1,2-diamines, brown solid (186mg, 10%), MS (ISN) m/z=339.5 [(M-H) -], mp 179 DEG C, the universal method (steps A) according to intermediate E is prepared from the fluoro-1-oil of mirbane (1.21g, 5.49mmol) of the bromo-2-of commercially available 4-and 4-methylsulfonyl-aniline (0.94g, 5.49mmol).
step B
This title compound, canescence foam (147mg, 79%), MS (ISP) m/z=353.3 [(M+H) +], the universal method (step B) according to intermediate E is prepared from the bromo-N2-of 4-(4-Metlianesulfonyl-phenyl)-benzene-1,2-diamines (steps A) (0.18g, 0.53mmol).
Embodiment 1
The p-tolyl of 1--6-(the p-tolyl of 2--2H-pyrazole-3-yl)-1H-benzoglyoxaline
To the p-tolyl of the bromo-1-of 6--1H-benzo [d] imidazoles (intermediate F) (100mg, 348 μm of ol) and the p-tolyl of 1--1H-pyrazoles-5-ylboronic acid (intermediate B) (91.5mg, 453 μm of ol) 1,2M sodium carbonate solution (696 μ l are added in mixture in 2-glycol dimethyl ether (3ml), 1.39mmol), and by reaction mixture argon gas purge 10min in ultra sonic bath.In stirring the mixture to this, add tetrakis triphenylphosphine palladium (0) (80.5mg, 69.6 μm of ol) in room temperature, and make reaction mixture under reflux conditions stir 15h.Reaction mixture is cooled to room temperature, pours in water (20ml) also with ethyl acetate (2x20ml) extraction.Organic layer washed with brine (1x 20ml) washing merged, dry (MgSO 4) and evaporate.Thick material (200mg) is by the flash chromatography (heptane/ethyl acetate 1: 1) on silica gel with from diethyl ether/heptane grinding purifying, obtain title compound, for pale solid (55mg, 43%), MS (ISP) m/z=365.2 [(M+H) +], mp 165 DEG C.
Embodiment 2
1-phenyl-6-(2-phenyl-2H-pyrazole-3-yl)-1H-benzoglyoxaline
This title compound, pale solid (36mg, 29%), MS (ISP) m/z=337.3 [(M+H) +], mp 194 DEG C, according to the universal method of embodiment 1 from the bromo-1-phenyl of 6--1H-benzo [d] imidazoles (intermediate E) (100ng, 366 μm of ol) and commercially available 1-phenyl-1H-pyrazoles-5-ylboronic acid [CAS No.1238702-56-1] (89.5mg, 476 μm of ol) preparation.
Embodiment 3
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-phenyl-1H-benzoglyoxaline
This title compound, pale solid (39mg, 30%), MS (ISP) m/z=355.2 [(M+H) +], mp 201 DEG C, according to the universal method of embodiment 1 from the bromo-1-phenyl of 6--1H-benzo [d] imidazoles (intermediate E) (100mg, 366 μm of ol) and 1-(the fluoro-phenyl of 4-)-1H-pyrazoles-5-ylboronic acid (intermediate A) (98.0mg, 476 μm of ol) preparation.
Embodiment 4
1-phenyl-6-(the p-tolyl of 2--2H-pyrazole-3-yl)-1H-benzoglyoxaline
This title compound, canescence foam (36mg, 28%), MS (ISP) m/z=351.3 [(M+H) +], according to the universal method of embodiment 1 from the bromo-1-phenyl of 6--1H-benzo [d] imidazoles (intermediate E) (100mg, 366 μm of ol) and the p-tolyl of 1--1H-pyrazoles-5-ylboronic acid (intermediate B) (96.2mg, 476 μm of ol) preparation.
Embodiment 5
6-(2-phenyl-2H-pyrazole-3-yl) the p-tolyl of-1--1H-benzoglyoxaline
This title compound, pale solid (27mg, 22%), MS (ISP) m/z=351.3 [(M+H) +], mp 146 DEG C, according to the universal method of embodiment 1 from the p-tolyl of the bromo-1-of 6--1H-benzo [d] imidazoles (intermediate F) (100mg, 348 μm of ol) and commercially available 1-phenyl-1H-pyrazoles-5-ylboronic acid [CAS No.1238702-56-1] (85.1mg, 453 μm of ol) preparation.
Embodiment 6
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl] the p-tolyl of-1--1H-benzoglyoxaline
This title compound, pale solid (22mg, 17%), MS (ISP) m/z=369.2 [(M+H) +], mp 149 DEG C, according to the universal method of embodiment 1 from the p-tolyl of the bromo-1-of 6--1H-benzo [d] imidazoles (intermediate F) (100mg, 348 μm of ol) and 1-(the fluoro-phenyl of 4-)-1H-pyrazoles-5-ylboronic acid (intermediate A) (93.3mg, 453 μm of ol) preparation.
Embodiment 7
1-(the fluoro-phenyl of 4-)-6-(2-phenyl-2H-pyrazole-3-yl)-1H-benzoglyoxaline
This title compound, brown solid (26mg, 21%), MS (ISP) m/z=355.2 [(M+H) +], mp 194 DEG C, according to the universal method of embodiment 1 from the bromo-1-of 6-(the fluoro-phenyl of 4-)-1H-benzo [d] imidazoles (intermediate G) (100mg, 344 μm of ol) and commercially available 1-phenyl-1H-pyrazoles-5-ylboronic acid [CAS No.] 238702-56-1] (83.9mg, 447 μm of ol) preparation.
Embodiment 8
1-(the fluoro-phenyl of 4-)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
This title compound, white solid (40mg, 31%), MS (ISP) m/z=373.1 [(M+H) +], mp 173 DEG C, according to the universal method of embodiment 1 from the bromo-1-of 6-(the fluoro-phenyl of 4-)-1H-benzo [d] imidazoles (intermediate G) (100mg, 344 μm of ol) and 1-(the fluoro-phenyl of 4-)-1H-pyrazoles-5-ylboronic acid (intermediate A) (92.0mg, 447 μm of ol) preparation.
Embodiment 9
1-(the fluoro-phenyl of 4-)-6-(the p-tolyl of 2--2H-pyrazole-3-yl)-1H-benzoglyoxaline
This title compound, light brown foam (78mg, 61%), MS (ISP) m/z=369.2 [(M+H) +], according to the universal method of embodiment 1 from the bromo-1-of 6-(the fluoro-phenyl of 4-)-1H-benzo [d] imidazoles (intermediate G) (100mg, 344 μm of ol) and the p-tolyl of 1--1H-pyrazoles-5-ylboronic acid (intermediate B) (90.2mg, 447 μm of ol) preparation.
Embodiment 10
1-(the fluoro-phenyl of 4-)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
This title compound, yellow solid (45mg, 31%), MS (ISP) m/z=423.5 [(M+H) +], mp 167 DEG C, according to the universal method of embodiment 1 from the bromo-1-of 6-(the fluoro-phenyl of 4-)-1H-benzo [d] imidazoles (intermediate G) (100mg, 344 μm of ol) and 1-(4-trifluoromethyl-phenyl)-1H-pyrazoles-5-ylboronic acid (intermediate C) (96.7mg, 378 μm of ol) preparation.
Embodiment 11
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(the fluoro-phenyl of 4-)-1H-benzoglyoxaline
This title compound, pale solid (28mg, 21%), MS (ISP) m/z=389.4 [(M+H) +], mp 180 DEG C, according to the universal method of embodiment 1 from the bromo-1-of 6-(the fluoro-phenyl of 4-)-1H-benzo [d] imidazoles (intermediate G) (100mg, 344 μm of ol) and 1-(the chloro-phenyl of 4-)-1H-pyrazoles-5-ylboronic acid (intermediate D) (84.0mg, 378 μm of ol) preparation.
Embodiment 12
1-(the chloro-phenyl of 4-)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
This title compound, brown solid (56mg, 39%), MS (ISP) m/z=439.4 [(M+H) +], mp 198 DEG C, according to the universal method of embodiment 1 from the bromo-1-of 6-(the chloro-phenyl of 4-)-1H-benzo [d] imidazoles (intermediate H) (100mg, 325 μm of ol) and 1-(4-trifluoromethyl-phenyl)-1H-pyrazoles-5-ylboronic acid (intermediate C) (91.6mg, 358 μm of ol) preparation.
Embodiment 13
1-(the chloro-phenyl of 4-)-6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
This title compound, brown solid (29mg, 22%), MS (ISP) m/z=405.4 [(M+H) +], mp 182 DEG C, according to the universal method of embodiment 1 from the bromo-1-of 6-(the chloro-phenyl of 4-)-1H-benzo [d] imidazoles (intermediate H) (100mg, 325 μm of ol) and 1-(the chloro-phenyl of 4-)-1H-pyrazoles-5-ylboronic acid (intermediate D) (79.6mg, 358 μm of ol) preparation.
Embodiment 14
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-trifluoromethyl-phenyl)-1H-benzoglyoxaline
This title compound, brown solid (37mg, 29%), MS (ISP) m/z=439.4 [(M+H) +], mp 196 DEG C, according to the universal method of embodiment 1 from the bromo-1-of 6-(4-trifluoromethyl-phenyl)-1H-benzo [d] imidazoles (intermediate compound I) (100mg, 293 μm of ol) and 1-(the chloro-phenyl of 4-)-1H-pyrazoles-5-ylboronic acid (intermediate D) (71.7mg, 322 μm of ol) preparation.
Embodiment 15
1-(2,4-difluorophenyl)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
This title compound, pale solid (48mg, 34%), MS (ISP) m/z=441.4 [(M+H) +], mp 129 DEG C, according to the universal method of embodiment 1 from the bromo-1-(2 of 6-, 4-difluorophenyl)-1H-benzo [d] imidazoles (intermediate K) (100mg, 324 μm of ol) and 1-(4-trifluoromethyl-phenyl)-1H-pyrazoles-5-ylboronic acid (intermediate C) (91.1mg, 356 μm of ol) preparation.
Embodiment 16
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(2,4-difluorophenyl)-1H-benzoglyoxaline
This title compound, pale solid (29mg, 22%), MS (ISP) m/z=407.4 [(M+H) +], mp 133 DEG C, according to the universal method of embodiment 1 from the bromo-1-(2 of 6-, 4-difluorophenyl)-1H-benzo [d] imidazoles (intermediate K) (100mg, 324 μm of ol) and 1-(the chloro-phenyl of 4-)-1H-pyrazoles-5-ylboronic acid (intermediate D) (79.2mg, 356 μm of ol) preparation.
Embodiment 17
1-(2,4-difluorophenyl)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
This title compound, brown solid (69mg, 55%), MS (ISP) m/z=391.5 [(M+H) +], mp 152 DEG C, according to the universal method of embodiment 1 from the bromo-1-(2 of 6-, 4-difluorophenyl)-1H-benzo [d] imidazoles (intermediate K) (100mg, 324 μm of ol) and 1-(the fluoro-phenyl of 4-)-1H-pyrazoles-5-ylboronic acid (intermediate A) (79.9mg, 388 μm of ol) preparation.
Embodiment 18
6-12-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-trifluoromethyl-phenyl)-1H-benzoglyoxaline
This title compound, brown solid (67mg, 54%), MS (ISP) m/z=423.3 [(M+H)+], mp 204 DEG C, according to the universal method of embodiment 1 from the bromo-1-of 6-(4-trifluoromethyl-phenyl)-1H-benzo [d] imidazoles (intermediate compound I) (100mg, 293 μm of ol) and 1-(the fluoro-phenyl of 4-)-1H-pyrazoles-5-ylboronic acid (intermediate A) (72.5mg, 352 μm of ol) preparation.
Embodiment 19
1-(the chloro-phenyl of 4-)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
This title compound, pale solid (44mg, 35%), MS (ISP) m/z=389.4 [(M+H) +], mp 173 DEG C, according to the universal method of embodiment 1 from the bromo-1-of 6-(the chloro-phenyl of 4-)-1H-benzo [d] imidazoles (intermediate H) (100mg, 325 μm of ol) and 1-(the fluoro-phenyl of 4-)-1H-pyrazoles-5-ylboronic acid (intermediate A) (80.3mg, 390 μm of ol) preparation.
Embodiment 20
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-pyridin-4-yl-1H-benzoglyoxaline
This title compound, pale solid (62mg, 48%), MS (ISP) m/z=356.4 [(M+H) +], mp 199 DEG C, according to the universal method of embodiment 1 from the bromo-1-pyridin-4-yl of 6--1H-benzoglyoxaline (intermediate L) (100mg, 365 μm of ol) and 1-(the fluoro-phenyl of 4-)-1H-pyrazoles-5-ylboronic acid (intermediate A) (90.2mg, 438 μm of ol) preparation.
Embodiment 21
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-pyridin-4-yl-1H-benzoglyoxaline
This title compound, white solid (50mg, 37%), MS (ISP) m/z=372.4 [(M+H) +], mp 203 DEG C, according to the universal method of embodiment 1 from the bromo-1-pyridin-4-yl of 6--1H-benzoglyoxaline (intermediate L) (100mg, 365 μm of ol) and 1-(the chloro-phenyl of 4-)-1H-pyrazoles-5-ylboronic acid (intermediate D) (97.4mg, 438 μm of ol) preparation.
Embodiment 22
1-(the fluoro-phenyl of the chloro-2-of 4-)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
This title compound, white solid (46mg, 37%), MS (ISP) m/z=407.5 [(M+H) +], mp 153 DEG C, according to the universal method of embodiment 1 from the bromo-1-of 6-(the fluoro-phenyl of the chloro-2-of 4-)-1H-benzo [d] imidazoles (intermediate M) (100mg, 307 μm of ol) and 1-(the fluoro-phenyl of 4-)-1H-pyrazoles-5-ylboronic acid (intermediate A) (76.0mg, 369 μm of ol) preparation.
Embodiment 23
1-(the fluoro-phenyl of the chloro-2-of 4-)-6-12-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
This title compound, white solid (23mg, 18%), MS (ISP) m/z=423.4 [(M+H) +], mp 158 DEG C, according to the universal method of embodiment 1 from the bromo-1-of 6-(the fluoro-phenyl of the chloro-2-of 4-)-1H-benzo [d] imidazoles (intermediate M) (100mg, 307 μm of ol) and 1-(the chloro-phenyl of 4-)-1H-pyrazoles-5-ylboronic acid (intermediate D) (82.1mg, 369 μm of ol) preparation.
Embodiment 24
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-methoxyl group-phenyl)-1H-benzoglyoxaline
This title compound, pale solid (34mg, 27%), MS (ISP) m/z=385.5 [(M+H) +], mp 143 DEG C, according to the universal method of embodiment 1 from the bromo-1-of 6-(4-methoxyl group-phenyl)-1H-benzo [d] imidazoles (intermediate N) (100mg, 330 μm of ol) and 1-(the fluoro-phenyl of 4-)-1H-pyrazoles-5-ylboronic acid (intermediate A) (81.6mg, 396 μm of ol) preparation.
Embodiment 25
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-methoxyl group-phenyl)-1H-benzoglyoxaline
This title compound, pale solid (16mg, 12%), MS (ISP) m/z=401.5 [(M+H) +], mp 163 DEG C, according to the universal method of embodiment 1 from the bromo-1-of 6-(4-methoxyl group-phenyl)-1H-benzo [d] imidazoles (intermediate N) (100mg, 330 μm of ol) and 1-(the chloro-phenyl of 4-)-1H-pyrazoles-5-ylboronic acid (intermediate D) (88.1mg, 396 μm of ol) preparation.
Embodiment 26
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-Metlianesulfonyl-phenyl)-1H-benzoglyoxaline
This title compound, white solid (12mg, 14%), MS (ISP) m/z=433.4 [(M+H) +]; mp 247 DEG C; according to the universal method of embodiment 1 from the bromo-1-of 6-(4-Metlianesulfonyl-phenyl)-1H-benzo [d] imidazoles (intermediate O) (70mg; 199 μm of ol) and 1-(the fluoro-phenyl of 4-)-1H-pyrazoles-5-ylboronic acid (intermediate A) (49.2mg, 239 μm of ol) preparation.
Embodiment 27
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-Metlianesulfonyl-phenyl)-1H-benzoglyoxaline
This title compound, white solid (13mg, 15%), MS (ISP) m/z=449.4 [(M+H) +]; mp 280 DEG C; according to the universal method of embodiment 1 from the bromo-1-of 6-(4-Metlianesulfonyl-phenyl)-1H-benzo [d] imidazoles (intermediate O) (70mg; 199 μm of ol) and 1-(the chloro-phenyl of 4-)-1H-pyrazoles-5-ylboronic acid (intermediate D) (53.2mg, 239 μm of ol) preparation.
Embodiment 28
1-(the fluoro-phenyl of 4-)-6-(3-phenyl-3H-imidazol-4 yl)-1H-benzoglyoxaline
Commercially available 1-phenyl-1H-imidazoles (50.5mg is added in flame-dried reaction flask, 0.35mmol), acid chloride (II) (7.86mg, 35.0 μm of ol), cesium fluoride (106mg, 0.7mmol), triphenylarsine (21.4mg, 70.0 μm of ol) and the bromo-1-of 6-(the fluoro-phenyl of 4-)-1H-benzo [d] imidazoles (intermediate G) (204mg, 0.7mmol).Reaction flask is vacuumized, and backfills with argon gas, and this process is repeated twice.Under argon gas stream, DMF (1.75ml) is added continuously by syringe afterwards in room temperature.Gained mixture is made to stir 48h at 140 DEG C under an argon.Afterwards reaction mixture is cooled to room temperature, pours in water (20ml), extract by ethyl acetate (2x 30ml) and use salt solution (20ml) to wash.By the organic layer drying (MgSO merged 4) and evaporate.Crude product is by the flash chromatography [methylene dichloride/MeOH (0-3%)] on silica gel and carry out purifying from dichloromethane/hexane crystallization, obtain title compound, for pale solid (23mg, 19%), MS (ISP) m/z=355.1 [(M+H) +], mp 216 DEG C.
Embodiment 29
6-[3-(the chloro-phenyl of 4-)-3H-imidazol-4 yl]-1-(the fluoro-phenyl of 4-)-1H-benzoglyoxaline
This title compound, pale solid (20mg, 15%), MS (ISP) m/z=389.5 [(M+H) +], mp 254 DEG C, according to the universal method of embodiment 28 from the bromo-1-of 6-(the fluoro-phenyl of 4-)-1H-benzo [d] imidazoles (intermediate G) (204mg, 0.7mmol) with the preparation of commercially available 1-(the chloro-phenyl of 4-)-1H-imidazoles (62.5mg, 0.35mmol).
Embodiment 30
1-(the fluoro-phenyl of 4-)-6-[3-(the fluoro-phenyl of 4-)-3H-imidazol-4 yl]-1H-benzoglyoxaline
This title compound, brown solid (26mg, 20%), MS (ISP) m/z=373.5 [(M+H) +], mp 247 DEG C, according to the universal method of embodiment 28 from the bromo-1-of 6-(the fluoro-phenyl of 4-)-1H-benzo [d] imidazoles (intermediate G) (204mg, 0.7mmol) with the preparation of commercially available 1-(the fluoro-phenyl of 4-)-1H-imidazoles (56.8mg, 0.35mmol).

Claims (19)

1. the compound of formula I
Wherein
R 1hydrogen, low alkyl group, halogen or the low alkyl group be optionally substituted by halogen;
R 2it is hydrogen or halogen;
X 1n or CH;
X 2n or CH;
Precondition is X 1or X 2in only one be N;
X 3c (R) or N;
And R is hydrogen, low alkyl group, halogen, the low alkyl group be optionally substituted by halogen, lower alkoxy or SO 2-low alkyl group;
Or its medicinal acid addition salt, racemic mixture or its corresponding enantiomer and/or optical isomer.
2. the compound of formula IA according to claim 1,
Wherein
R 1hydrogen, low alkyl group, halogen or the low alkyl group be optionally substituted by halogen;
R 2it is hydrogen or halogen;
X 3c (R) or N;
And R is hydrogen, low alkyl group, halogen, the low alkyl group be optionally substituted by halogen, lower alkoxy or SO 2-low alkyl group;
Or its medicinal acid addition salt, racemic mixture or its corresponding enantiomer and/or optical isomer.
3. the compound of the formula IA any one of claim 1 or 2, wherein said compound is
The p-tolyl of 1--6-(the p-tolyl of 2--2H-pyrazole-3-yl)-1H-benzoglyoxaline
1-phenyl-6-(2-phenyl-2H-pyrazole-3-yl)-1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-phenyl-1H-benzoglyoxaline
1-phenyl-6-(the p-tolyl of 2--2H-pyrazole-3-yl)-1H-benzoglyoxaline
6-(2-phenyl-2H-pyrazole-3-yl) the p-tolyl of-1--1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl] the p-tolyl of-1--1H-benzoglyoxaline
1-(the fluoro-phenyl of 4-)-6-(2-phenyl-2H-pyrazole-3-yl)-1H-benzoglyoxaline
1-(the fluoro-phenyl of 4-)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
1-(the fluoro-phenyl of 4-)-6-(the p-tolyl of 2--2H-pyrazole-3-yl)-1H-benzoglyoxaline
1-(the fluoro-phenyl of 4-)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(the fluoro-phenyl of 4-)-1H-benzoglyoxaline
1-(the chloro-phenyl of 4-)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
1-(the chloro-phenyl of 4-)-6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-trifluoromethyl-phenyl)-1H-benzoglyoxaline
1-(2,4-difluorophenyl)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(2,4-difluorophenyl)-1H-benzoglyoxaline
1-(2,4-difluorophenyl)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-trifluoromethyl-phenyl)-1H-benzoglyoxaline
1-(the chloro-phenyl of 4-)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-pyridin-4-yl-1H-benzoglyoxaline
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-pyridin-4-yl-1H-benzoglyoxaline
1-(the fluoro-phenyl of the chloro-2-of 4-)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
1-(the fluoro-phenyl of the chloro-2-of 4-)-6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-methoxyl group-phenyl)-1H-benzoglyoxaline
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-methoxyl group-phenyl)-1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-Metlianesulfonyl-phenyl)-1H-benzoglyoxaline, or
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-Metlianesulfonyl-phenyl)-1H-benzoglyoxaline.
4. the compound of formula IA-1 as claimed in one of claims 1-3
Wherein
R 1hydrogen, low alkyl group, halogen or the low alkyl group be optionally substituted by halogen;
R 2it is hydrogen or halogen;
R is hydrogen, low alkyl group, halogen, the low alkyl group be optionally substituted by halogen, lower alkoxy or SO 2-low alkyl group,
Or its medicinal acid addition salt, racemic mixture or its corresponding enantiomer and/or optical isomer.
5. the compound of formula IA-1 as claimed in one of claims 1-4, wherein said compound is
The p-tolyl of 1--6-(the p-tolyl of 2--2H-pyrazole-3-yl)-1H-benzoglyoxaline
1-phenyl-6-(2-phenyl-2H-pyrazole-3-yl)-1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-phenyl-1H-benzoglyoxaline
1-phenyl-6-(the p-tolyl of 2--2H-pyrazole-3-yl)-1H-benzoglyoxaline
6-(2-phenyl-2H-pyrazole-3-yl) the p-tolyl of-1--1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl] the p-tolyl of-1--1H-benzoglyoxaline
1-(the fluoro-phenyl of 4-)-6-(2-phenyl-2H-pyrazole-3-yl)-1H-benzoglyoxaline
1-(the fluoro-phenyl of 4-)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
1-(the fluoro-phenyl of 4-)-6-(the p-tolyl of 2--2H-pyrazole-3-yl)-1H-benzoglyoxaline
1-(the fluoro-phenyl of 4-)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(the fluoro-phenyl of 4-)-1H-benzoglyoxaline
1-(the chloro-phenyl of 4-)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
1-(the chloro-phenyl of 4-)-6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-trifluoromethyl-phenyl)-1H-benzoglyoxaline
1-(2,4-difluorophenyl)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(2,4-difluorophenyl)-1H-benzoglyoxaline
1-(2,4-difluorophenyl)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-trifluoromethyl-phenyl)-1H-benzoglyoxaline
1-(the chloro-phenyl of 4-)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
1-(the fluoro-phenyl of the chloro-2-of 4-)-6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
1-(the fluoro-phenyl of the chloro-2-of 4-)-6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-methoxyl group-phenyl)-1H-benzoglyoxaline
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-methoxyl group-phenyl)-1H-benzoglyoxaline
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-Metlianesulfonyl-phenyl)-1H-benzoglyoxaline, or
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-(4-Metlianesulfonyl-phenyl)-1H-benzoglyoxaline.
6. the compound of formula IA-2 as claimed in one of claims 1-3
Wherein
R 1hydrogen, low alkyl group, halogen or the low alkyl group be optionally substituted by halogen;
R 2it is hydrogen or halogen;
Or its medicinal acid addition salt, racemic mixture or its corresponding enantiomer and/or optical isomer.
7. the compound of the formula IA-2 any one of claim 1-3 and 6, wherein said compound is
6-[2-(the fluoro-phenyl of 4-)-2H-pyrazole-3-yl]-1-pyridin-4-yl-1H-benzoglyoxaline, or
6-[2-(the chloro-phenyl of 4-)-2H-pyrazole-3-yl]-1-pyridin-4-yl-1H-benzoglyoxaline.
8. the compound of formula IB according to claim 1
Wherein
R 1hydrogen, low alkyl group, halogen or the low alkyl group be optionally substituted by halogen;
R 2it is hydrogen or halogen;
X 3c (R) or N;
And R is hydrogen, low alkyl group, halogen, the low alkyl group be optionally substituted by halogen, lower alkoxy or SO 2-low alkyl group,
Or its medicinal acid addition salt, racemic mixture or its corresponding enantiomer and/or optical isomer.
9. the compound any one of claim 1 or 8, described compound is
1-(the fluoro-phenyl of 4-)-6-(3-phenyl-3H-imidazol-4 yl)-1H-benzoglyoxaline
6-[3-(the chloro-phenyl of 4-)-3H-imidazol-4 yl]-1-(the fluoro-phenyl of 4-)-1H-benzoglyoxaline, or
1-(the fluoro-phenyl of 4-)-6-[3-(the fluoro-phenyl of 4-)-3H-imidazol-4 yl]-1H-benzoglyoxaline.
10. a method for the compound of the formula I limited any one of manufacturing claims 1 to 9, described method comprises:
Make the compound of formula 1
With the compound of formula 2
The compound of reaction production I
Further, if needed, the compound of acquisition is changed into medicinal acid addition salt.
11. compounds according to any one of claim 1 to 9 manufactured by method according to claim 10.
12. pharmaceutical compositions, described pharmaceutical composition comprises compound according to any one of claim 1 to 9 and pharmaceutical carrier and/or auxiliary material.
13. pharmaceutical compositions, described pharmaceutical composition comprises compound according to any one of claim 1 to 9 and pharmaceutical carrier and/or auxiliary material, described pharmaceutical composition is used for the treatment of schizophrenia, compulsive personality disorder, major depressive disorder, bipolar disorder, anxiety disorder, usual aging, epilepsy, retinal degeneration, traumatic brain injury, Spinal injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dull-witted, alzheimer's disease, mild cognitive impairment, the cognition dysfunction that chemotherapy causes, mongolism, autism spectrum disorder, hearing loss, tinnitus, spinocebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington Chorea, apoplexy, radiotherapy, chronic stress, neuroactive drug is alcohol such as, opiate, methyl amphetamine, the abuse of phencyclidine and Cocaine.
14. compounds according to any one of claim 1 to 9, described compound is used as therapeutic active substance.
15. compounds according to any one of claim 1 to 9, described compound is used as therapeutic active substance in the treatment of following disease: schizophrenia, compulsive personality disorder, major depressive disorder, bipolar disorder, anxiety disorder, usual aging, epilepsy, retinal degeneration, traumatic brain injury, Spinal injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dull-witted, alzheimer's disease, mild cognitive impairment, the cognition dysfunction that chemotherapy causes, mongolism, autism spectrum disorder, hearing loss, tinnitus, spinocebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington Chorea, apoplexy, radiotherapy, chronic stress, neuroactive drug is alcohol such as, opiate, methyl amphetamine, the abuse of phencyclidine and Cocaine.
16. compounds according to any one of claim 1 to 9 are for the preparation of the purposes of medicine, described being used for the treatment of property of medicine and/or prophylactic treatment schizophrenia, compulsive personality disorder, major depressive disorder, bipolar disorder, anxiety disorder, usual aging, epilepsy, retinal degeneration, traumatic brain injury, Spinal injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dull-witted, alzheimer's disease, mild cognitive impairment, the cognition dysfunction that chemotherapy causes, mongolism, autism spectrum disorder, hearing loss, tinnitus, spinocebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington Chorea, apoplexy, radiotherapy, chronic stress, neuroactive drug is alcohol such as, opiate, methyl amphetamine, the abuse of phencyclidine and Cocaine.
17. 1 kinds of methods being used for the treatment of or preventing following disease: schizophrenia, compulsive personality disorder, major depressive disorder, bipolar disorder, anxiety disorder, usual aging, epilepsy, retinal degeneration, traumatic brain injury, Spinal injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dull-witted, alzheimer's disease, mild cognitive impairment, the cognition dysfunction that chemotherapy causes, mongolism, autism spectrum disorder, hearing loss, tinnitus, spinocebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington Chorea, apoplexy, radiotherapy, chronic stress, neuroactive drug is alcohol such as, opiate, methyl amphetamine, the abuse of phencyclidine and Cocaine, described method comprise use significant quantity any one of claim 1 to 9 the compound that limits.
18. compounds according to any one of claim 1 to 9 are used for the treatment of or prevent the purposes of following disease: schizophrenia, compulsive personality disorder, major depressive disorder, bipolar disorder, anxiety disorder, usual aging, epilepsy, retinal degeneration, traumatic brain injury, Spinal injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dull-witted, alzheimer's disease, mild cognitive impairment, the cognition dysfunction that chemotherapy causes, mongolism, autism spectrum disorder, hearing loss, tinnitus, spinocebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington Chorea, apoplexy, radiotherapy, chronic stress, neuroactive drug is alcohol such as, opiate, methyl amphetamine, the abuse of phencyclidine and Cocaine.
19. invent as above.
CN201380050747.1A 2012-10-01 2013-09-27 As the benzimidazoles compound of CNS activity medicament Expired - Fee Related CN104703981B (en)

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Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10730842B2 (en) * 2015-09-03 2020-08-04 Arizona Board Of Regents On Behalf Of The University Of Arizona Small molecule inhibitors of DYRK1A and uses thereof
WO2018013430A2 (en) 2016-07-12 2018-01-18 Arisan Therapeutics Inc. Heterocyclic compounds for the treatment of arenavirus infection
BR112019024881A2 (en) * 2017-06-02 2020-06-16 Fujifilm Toyama Chemical Co., Ltd. AGENT TO AVOID OR TREAT SPINOCEREBELLAR ATAXIA
EP3632431A4 (en) 2017-06-02 2020-06-03 FUJIFILM Toyama Chemical Co., Ltd. Agent for preventing or treating brain atrophy
SG11201911519UA (en) 2017-06-02 2020-01-30 Fujifilm Toyama Chemical Co Ltd AGENT FOR REDUCING AMOUNT OF AMYLOID ß PROTEIN
US11541033B2 (en) 2017-06-02 2023-01-03 Fujifilm Toyama Chemical Co., Ltd. Agent for preventing or treating Alzheimer's disease
US20190060109A1 (en) * 2017-08-31 2019-02-28 Gregory Todd Johnson Method of Preventing Traumatic Brain Injury (TBI)
EP3705121B1 (en) 2017-10-30 2023-08-30 FUJIFILM Toyama Chemical Co., Ltd. Emopamil binding protein binding agent and use thereof
EP4069685A1 (en) * 2019-12-02 2022-10-12 F. Hoffmann-La Roche AG Alkynyl-(heteroaryl)-carboxamide hcn1 inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008046072A2 (en) * 2006-10-13 2008-04-17 The Board Of Regents Of The University Of Texas System Chemical inducers of neurogenesis
WO2012006419A2 (en) * 2010-07-07 2012-01-12 Board Of Regents Of The University Of Texas System Pro-neurogenic compounds

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1164134A1 (en) * 1995-04-21 2001-12-19 Neurosearch A/S Benzimidazole compounds and their use as modulators of the GABA A receptor complex
US7074801B1 (en) * 2001-04-26 2006-07-11 Eisai Co., Ltd. Nitrogen-containing condensed cyclic compound having a pyrazolyl group as a substituent group and pharmaceutical composition thereof
KR20070112276A (en) * 2005-03-16 2007-11-22 아벤티스 파마슈티칼스 인크. Dipyrazoles as central nervous system agents
CN101351461B (en) * 2005-12-27 2011-09-07 弗·哈夫曼-拉罗切有限公司 Aryl-isoxazol-4-yl-imidazole derivatives
BRPI0706726B8 (en) * 2006-01-24 2021-05-25 Janssen Pharmaceutica Nv 2-substituted benzimidazoles as selective androgen receptor modulators (sarms), pharmaceutical composition comprising them and process for preparing
TWI391381B (en) * 2006-03-24 2013-04-01 Neurosearch As Benzimidazole derivatives, pharmaceutical compositions containing the same, and use of the same for the manufacture of a medicament
WO2008016123A1 (en) * 2006-08-03 2008-02-07 Takeda Pharmaceutical Company Limited GSK-3β INHIBITOR
JP2009292782A (en) * 2008-06-06 2009-12-17 Asahi Kasei Pharma Kk Agent for promoting neurogenesis and/or neurotization
RS53416B (en) * 2009-03-10 2014-12-31 Takeda Pharmaceutical Company Limited Benzofuran derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008046072A2 (en) * 2006-10-13 2008-04-17 The Board Of Regents Of The University Of Texas System Chemical inducers of neurogenesis
WO2012006419A2 (en) * 2010-07-07 2012-01-12 Board Of Regents Of The University Of Texas System Pro-neurogenic compounds

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